1. Introduction

Mental disorders including depression, anxiety disorders, post-traumatic stress disorder (PTSD), schizophrenia, and dementia have an immense toll on the healthcare system and society at large (Brewster et al., 2023). More than 3.5 hundred million people live with depression and 3.74 hundred million people suffer from anxiety disorders globally (Romeo et al., 2020; Zeifman et al., 2021). Major depressive disorder (MDD) is characterized by the persistence of negative thoughts and emotions that disrupt mood, cognition, motivation, and behavior (Vargas et al., 2020). Core features of anxiety disorder include excessive fear and anxiety or avoidance of perceived threats that are persistent and harmful (Kalin, 2020; Penninx et al., 2021). PTSD is a maladaptive and debilitating mental disorder, characterized by re-experiencing, avoidance, negative emotions and thoughts, and hyperarousal in the months and years following exposure to severe trauma (Ressler et al., 2022). At present, there are many treatment measures for patients with depression and anxiety, including drug therapy, evidence-based psychotherapy, cognitive behavioral therapy, and neuromodulationtechnology (Carhart-Harris et al., 2021; Penninx et al., 2021). When it comes to the treatment of PTSD, treatments with the strongest support are prolonged behavioral exposure and cognitive processing therapy (Merians et al., 2023). However, even the best-performing drugs and instrumental treatments show modest efficacy, non-negligible side effects, discontinuation problems, and high relapse rates, highlighting the need for novel, improved treatments.

Psychedelics are serotonin 2A receptor (5-HT2AR) agonists including lysergic acid diethylamide (LSD), ayahuasca (active component N,Nʹ-dimethyltryptamine, DMT),phosphoryloxy-N,N-dimethyltryptamine (psilocybin) and serotonin transporter (SERT) inhibitor—3,4-methylenedioxymethamphetamine (MDMA), and they have been administered as sacraments since ancient times (Johnson et al., 2019). During the 1950s and 1960s, psychedelics were extensively investigated in psycholytic (low dose) and psychedelic (low to high dose) substance-assisted psychotherapy. Psychedelics can reduce morbidity in patients with various forms of depression and neuroses, anxiety disorders, personality disorders, sexual dysfunctions, and alcohol dependence (Reiff et al., 2020). Current behavioral and neuroimaging data show that psychedelics induce their psychological effects primarily via 5-HT2AR activation and modulate neural circuits involved in mood and affective disorders (Pędzich et al., 2022). Additional findings show that psychedelics enhance glutamate-driven neuroplasticity in animals and may provide a novel mechanism for the lasting symptom improvements observed in recent clinical trials of patients with mental disorders (Aleksandrova and Phillips, 2021).

Although evidence shows that psychedelics have a therapeutic effect on depression, their effectiveness varies across different types of psychedelics. Psilocybin therapy shows antidepressant potential, and Daws assessed the subacute impact of psilocybinon brain function in two clinical trials (an open-label trial and a double-blind phase II randomized controlled trial) of depression. In both trials, the antidepressant effects of psilocybin were rapid and sustained (Daws et al., 2022). The prototypical serotonergic hallucinogen LSD was used in the 1950s-1970s as an adjunct to psychotherapy (Passie et al., 2008). A published study showed the safety and efficacy of LSD-assisted psychotherapy in patients with anxiety associated with life-threatening diseases. After 12 months of LSD psychotherapy, 10 participants reported a reduction in anxiety (77.8%) and a rise in quality of life (66.7%) (Gasser et al., 2015). LSD has also been investigated as a treatment for several mental disorders, including alcoholism, opioid addiction, and anxiety and depression associated with terminal illness (Schmid et al., 2021). Ayahuasca, a natural psychedelic brew prepared from Amazonian plants and rich in DMT and harmine, induces subjective well-being and may therefore have antidepressant actions (Osório Fde et al., 2015). Palhano-Fontes et al. observed significant antidepressant effects of ayahuasca when compared to placebo in 29 patients with treatment-resistant depression (TRD) (Palhano-Fontes et al., 2019). MDMA is the main psychoactive substance in the party drug ecstasy, which is known to increase feelings of empathy and social engagement, heighten mood states, and facilitate the processing of difficult emotions (Holze et al., 2020). An observational study suggests that MDMA use is associated with a lower risk of depression (Jones and Nock, 2022). MDMA-assisted behavioral therapy is highly efficacious in individuals with severe PTSD including those with common comorbidities such as dissociation, depression, substance use disorders, and childhood trauma (Mitchell et al., 2021).

In this systematic review and meta-analysis, we synthesized the results of all clinical trials on psychedelic-assisted therapy or monotherapy published after 1960. We examined the effect sizes of psychedelics (LSD, ayahuasca, psilocybin, and MDMA) on mood disorders (depression, anxiety, negative emotions in people with substance-use disorders [SUD] and terminal illness), and other mental disorders (such as alcohol use disorder and PTSD) at the primary endpoints. We also analyzed the emotional effects of psychedelics on healthy subjects to evaluate the safety of psychedelics. Finally, we discussed the side effects of psychedelics in the treatment of mental illness. Overall, we aimed to synthesize the best available clinical evidence on these therapies and propose directions for future research.

2. Methods

The protocol for this review was preregistered with PROSPERO (CRD42022369783). The search and selection strategy was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., 2021).

2.1. Literature search

Web of Science, Embase, EBSCO, and PubMed were systematically searched in February 2024. Search string used was ((Hallucinogens[MeSH Terms] OR (Hallucinogenic Agents) OR (Psychedelic Agents) OR (Psychotomimetic Agents) OR (Hallucinogenic Substances) OR (Hallucinogenic Drugs) OR (psychedelic) OR (ecstasy) OR (MDMA) OR (3,4-methylenedioxymethamphetamine) OR (psilocybin) OR (Lysergic Acid Diethylamide) OR (LSD) OR (ayahuasca) OR (dimethyltryptamine) OR (DMT) OR (mescaline) OR (2,5-dimethoxy-4-iodoamphetamine) OR (DOI)) AND (psychiatr* OR "mental*" OR neuropsych* OR "personality disorder*" OR "mood disorder*" OR "affective disorder*" OR "depressi*" OR anxi* OR post-traumatic* OR PTSD OR "bipolar disorder*" OR schizophren* OR autis* OR ADHD OR "eating disorder*" OR "substance abuse" OR "substance dependence" OR "alcohol use" OR anorexia OR bulim* OR schizoaffect* OR psychosis OR antipsychotic* OR antidepressant*)) AND ((randomized controlled trial[Publication Types]) OR (controlled clinical trial[Publication Types]) OR (randomized[Title and/or abstract]) OR (placebo[Title and/or abstract]) OR (randomly[Title and/or abstract]) OR (clinical trial[Title and/or abstract]) OR (groups[Title and/or abstract]) OR ("open label"[Title and/or abstract])). Study selection was performed by three independent researchers (Y.Y., D.G., and T.S.L.). Any discrepancies were resolved by discussion.

2.2. Inclusion and exclusion criteria

The studies included were selected according to the following criteria: 1) They were published in English in a peer-reviewed journal. 2) The studies included participants with mood disorders, and patients diagnosed using the DSM-IV or DSM-V who met criteria for anxiety, mood, generalized anxiety disorder (GAD), MDD, recurrent MDD, or life-threatening illness related anxiety/depression. Patients also had been diagnosed with TRD of at least moderate severity, with most meeting the criteria for severe depression (HAM-D > 24; BDI > 30). Participants with a DSM-IV diagnosis of anxiety and/or mood symptoms were included. SUD patients (who met the criteria for admission into treatment at Takiwasi (Giovannetti et al., 2020)) were evaluated using the Beck Anxiety Inventory (BAI) and the Beck Depression Inventory (BDI). Alcohol use disorder (AUD) patients met DSM-IV criteria for alcohol dependence and had at least 4 heavy drinking days during the 30 days before screening (defined as 5 or more drinks in a day for a man and 4 or more drinks in a day for a woman). PTSD patients met DSM-5 criteria for current PTSD (CAPS-5 Total Severity Score of 35 or greater at baseline). The participants were exposed to psychedelic as an add-on treatment or monotherapy. 3) Studies assessing adverse reactions related to psychedelic use were also included. 4) Experimental studies: randomized controlled clinical trials (RCT), quasi-RCTs, and controlled clinical trials. Both single-group and between-group designs were eligible. Because of the difficulty of blinding psychedelics, a large number of clinical studies have used non-RCT research methods such as single group pre-post designs. We included these non-RCT studies to avoid missing this part of the evidence. 5) Psychological scales were measured as an outcome before and after psychedelic treatment.

Studies were excluded using the following criteria: 1) Animal studies, 2) outdated data published before 1960, 3) studies published as abstracts only, conference abstracts, case series and case reports, observational studies, and cross-sectional surveys. Other exclusions were: 4) missing data necessary for computing effect sizes, and 5) lack of baseline or relevant control groups or objective measurement scales.

Articles about the effects of different psychedelics on healthy subjects and articles that could not be used for meta-analysis because data could not be extracted or the number of studies on related diseases was too small were used as systematic reviews.

2.3. Data extraction

The primary outcome of interest was the treatment effects on mental disorders, as indicated by pre-/post-scores of symptomatology using standard measures, as well as the statistical significance of results. All effect sizes were calculated as standardized mean differences between groups on primary outcome measures, comparing the active treatment groups to the control (placebo) groups or comparing the active treatment group before and after the treatment. We extracted the following data from the study: authors, year of publication, type of study design (single group pre/post or placebo-controlled), specific disorder (depression, anxiety, or substance-use disorders, alcohol use disorder, and PTSD), psychedelic drug, primary outcome measure, sample size, drug dose, number of dosing sessions, type of control group, primary endpoint (first assessment after treatment and the end point of the follow-up period) and main findings for that endpoint and side effects. We also extracted participants’ demographics (sex, average age). We selected symptom scales based on those most frequently used to assess anxiety and depression in the literature. If an article used multiple scales to evaluate an indicator, the scale used most frequently in the literature was selected. We selected the following scales for depression: Back Depression Inventory (BDI), Hamilton Anxiety and Depression Scale-Depression (HADS-D), Montgomery-Asberg Depression Rating Scale (MADRS), Quick Inventory of Depression Symptomatology Self Report (QIDS-SR-16). For Anxiety, we used: State-Trait Anxiety Inventory (STAI) and Beck Anxiety Inventory (BAI). For Suicide, we used: Montgomery-asberg Depression Rating Scale-Suicide (MADRS-SI) and Social Introversion (SI). We used for AUD: percentage of heavy drinking days; for PTSD: Clinical-Administered Post Traumatic Stress Disorder Scale (CAPS) in sequence. When data were not available in these articles, we contacted the corresponding authors of each included trial by email to improve data collection. When authors did not respond after contact, we performed a graphical extraction and used Plot Dligitizer to calculate the standardized mean differences. This extraction was performed by both reviewers. Any discrepancies were resolved by discussion.

2.4. Statistical analyses

In cases where continuous outcomes were reported, Hedges’ g was used to handle the heterogeneity of different measurement or scale for same outcome and was calculated as effect size by means, standard deviations, and sample sizes using Stata MP 17 (StataCorp, College Station, TX). In contrast, for categorical outcomes were reported, such as studies that only give the number of people in remission before and after treatment, the odds ratio (ORs) was used for the calculations. For the RCTs studies we used the difference between the control and experimental groups for calculations, whereas for the single group pre-post studies we used the mean change from baseline. For studies where multiple measurement time points existed, we used the difference from baseline at the last time point of follow-up in order to assess the long-term (or discreet) effects of psychedelic. The effect sizes describe treatment effects on mental disorders, such that larger negative numbers indicate stronger efficacy on symptoms. We included studies that reported the outcomes by the following: (a) psychedelics dose and (b) separately for sessions before and after cross-over, with each outcome having their data combined. The pooled standardized mean differences (SMD) and 95% confidential interval (95% CI) for continues variables and ORs and 95% CI for categorical variables were estimated in the meta-analysis. Additionally, all analyses were performed with a random-effect model, which considers both between-study and within-study variability. The heterogeneity was quantified using the I² statistic, and categorized as low (I² < 25%), moderate (I² = 25–50%), or high (I² > 50%). Subgroup analyses were performed on different psychedelics, disorder types, duration of efficacy, and efficacy index. Meta-regression was used to explore the heterogeneity of the results, including dose, age of the subjects, female proportion, and number of study participants. Two different analyses were used to evaluate the potential impact of publication bias on the present meta-analysis—Funnel plots and Egger's regression test. The sensitivity analysis was also conducted by eliminating each study one at a time to evaluate the stability of the results.

3. Results

3.1. Study selection

A flow diagram shows the specific steps in the article selection procedure (Fig. 1). Initially, a total of 17,780 citations from different databases were obtained. Redundance and duplicates were removed, and the remaining 14,396 titles and/or abstracts were screened. Based on the inclusion and exclusion criteria, 126 articles were finally included in the study, of which 59 were used for meta-analysis and 67 were used for systematic reviews.

3.2. Characteristics of studies

Table 1 summarizes the studies in this systematic review and meta-analysis: MDMA has the largest number of articles on treating PTSD (N = 18); Ayahuasca (N = 7) and psilocybin (N = 28) have the largest number of articles on treating mood disorders; LSD has six articles on treating mood disorders and six on alcoholism. The main characteristics of each study included in meta-analysis, as detailed in the Methods, are outlined in Table 2 (Agin-Liebes, 2021; Agin-Liebes et al., 2020; Barone et al., 2019; Bogenschutz et al., 2015, 2022; Bowen et al., 1970; Carhart-Harris et al., 2021, 2018, 2016a; D'Souza et al., 2022; Danforth et al., 2018; Davis et al., 2021; Daws et al., 2022; Dos Santos et al., 2021; Feduccia et al., 2021; Gasser et al., 2014, ; 2015; Giovannetti et al., 2020; Goodwin et al., 2022; G.M. Goodwin et al., 2023a, 2023b; Gorman et al., 2020; Griffiths et al., 2016; Grob et al., 2011; Gukasyan et al., 2022; Hollister et al., 1969; Holze et al., 2023; Jardim et al., 2021; Johnson et al., 2017; Lewis et al., 2023; Ludwig et al., 1969; Lyons and Carhart-Harris, 2018; Majumder et al., 2012; Mitchell et al., 2021, 2023; Mithoefer et al., 2019, 2018; Murphy et al., 2021; Oehen et al., 2013; Osório Fde et al., 2015; Ot'alora et al., 2018; Pahnke et al., 1970; Palhano-Fontes et al., 2019; Ponte et al., 2021; Raison et al., 2023; Ross et al., 2021, 2016; Sanches et al., 2016; Sloshower et al., 2023; Smart et al., 1966; Stroud et al., 2018; Tomsovic and Edwards, 1970; van der Kolk et al., 2024; von Rotz et al., 2023; Wagner et al., 2017; Wall et al., 2023; Wang et al., 2021; Wolfson et al., 2020; Zeifman et al., 2024, 2021). Supplementary Table 1 (Apud et al., 2023; Atila et al., 2023; Barba et al., 2022; Brewerton et al., 2022; Christie et al., 2022; D'Souza et al., 2022; Dominguez-Clave et al., 2019; Doss et al., 2021; Gouzoulis-Mayfrank et al., 2005; Grof et al., 1973; Johnson et al., 2014; Kast, 1967; Kast and Collins, 1964; Moreno et al., 2006; Nicholas et al., 2022; Pahnke et al., 1969; Roseman et al., 2018; Schindler et al., 2021, 2022; Schneier et al., 2023; Sessa et al., 2021, 2019; Shnayder et al., 2023; Singleton et al., 2023; Stauffer et al., 2021; Timmermann et al., 2024; Vogt et al., 2023; Weiss et al., 2023; Zeifman et al., 2023) summarized the main characteristics of each of the studies included in the systematic review that could not be used in the meta-analysis because of the unavailability of primary data or the number of studies on related diseases was too small. This part covered psychedelics for the treatment of specific symptoms and other mental disorders, which will be discussed in detail in Part III. Supplementary Table 2 (Baggott et al., 2016; Barrett et al., 2020; Becker et al., 2022; Bedi et al., 2010; Bershad et al., 2019; Bosker et al., 2010; Carbonaro et al., 2018; de Wit et al., 2022; Dolder et al., 2018, 2016; Doss et al., 2018; Dudysová et al., 2020; Griffiths et al., 2011; Grob et al., 1996; Hutten et al., 2020; Hysek et al., 2013, 2014; Kiraga et al., 2022; Kometer et al., 2012; Kraehenmann et al., 2015; Kuypers et al., 2008, 2018; Liechti et al., 2000a, 2000b; Marschall et al., 2022; Perkins et al., 2022; Perna et al., 2014; Pokorny et al., 2017; Ramaekers et al., 2021; Rucker et al., 2022; Santos et al., 2007; Schmid et al., 2014; Schmid and Liechti, 2018; Uthaug et al., 2021; van Wel et al., 2012; Wardle and de Wit, 2014) provided a summary of the main features of studies on the effects of different psychedelics on healthy subjects as another part of the systematic review, which involved 40 studies.

Most studies used only a single or two doses and the largest number focused on psilocybin (43.6%) with 29.9% involving MDMA, 14.9% involving LSD, and 11.5% involving ayahuasca. These psychedelics were used in five major groups of people: depressive disorders, anxiety disorders, PTSD, substance-use disorders related anxiety/depression, and life-threatening illness related anxiety/depression. The latter two groups were usually associated with adverse psychological states. Two subtypes of depressive disorder were classified as MDD and recurrent MDD/TRD, respectively.

The average post-treatment evaluation time was 11.97 weeks (SD = 11.88, range = 0 to 52). For studies with a follow-up assessment (51.7%), the last follow-up occurred 9.65 months on average (SD = 12.50, range = 0.5 to 54) after treatment. Except for some articles (Bogenschutz et al., 2022; Goodwin et al., 2022; G.M. Goodwin et al., 2023a, 2023b; Hollister et al., 1969; Ludwig et al., 1969; Mitchell et al., 2021, 2023; Mithoefer et al., 2019; Pahnke et al., 1970; Raison et al., 2023; Tomsovic and Edwards, 1970), most of them used small sample sizes with an average of 23.46 participants (SD = 13.30, range = 3 to 52). The mean age was 43.74 years old and 53.94% of the samples were female. A more detailed description will be displayed in the subgroup analysis.

3.3. Part I: psychedelics for the treatment of mood disorders

3.3.1. Overall effect sizes

We conducted analyses of therapeutic effects across these 35 studies for four psychedelics: LSD, ayahuasca, psilocybin, and MDMA (Fig. 2). Overall, different psychedelics have improved negative mood to some extent. Specifically, psilocybin (Hedges’ g = −1.49, 95% CI [−1.67, −1.30], I2 = 52.93%, p < 0.001) in 22 studies showed the strongest therapeutic effect among four psychedelics, followed by ayahuasca (Hedges’ g= −1.34, 95% CI [−1.86, −0.82], I2 = 73.08%, p < 0.001) in 7 studies and MDMA (Hedges’ g= −0.83, 95% CI [−1.33, −0.32], I2 = 00.00%, p = 0.92) in 3 studies, while the effect of LSD (Hedges’ g = −0.65, 95% CI [−1.03, −0.27], I2=37.89%, p = 0.13) in another 3 studies was lower possibly due to the small number of included studies. Due to a relatively comprehensive study collection, this meta-analysis included clinical studies from a wide range of study types after excluding case series and case reports, observational studies, and cross-sectional surveys. Therefore, we conducted a subgroup analysis to discuss the effects of study designs of different psychedelics for the treatment of mood disorder. Specifically, four types were categorized: 1″Single group pre-post", 2″Placebo-controlled", 3″Low dose psychedelic-controlled", 4″Positive drug-controlled". It was found that the clinical studies of LSD contained only single group pre-post study designs (Hedges’ g = −0.65, 95% CI [−1.03, −0.27], I² = 37.89%, p = 0.13) (Fig. 2A). Single group pre-post studies (Hedges’ g = −1.40, 95% CI [−1.90, −0.90], I² = 60.39%, p = 0.03) on ayahuasca reported stronger efficacy than placebo-controlled (Hedges’ g = −1.20, 95% CI [−3.04, 0.65], I² = 90.64%, p = 0.00) (Fig. 2B). A similar condition was seen in the MDMA studies which showed that single group pre-post studies (Hedges’ g = −0.88, 95% CI [−1.76, 0.00]) was slightly higher than placebo-controlled (Hedges’ g = −0.80, 95% CI [−1.42, −0.19], I² = 00.64%, p = 0.79) (Fig. 2C). Psilocybin had the richest study design encompassing four of types mentioned above (Fig. 2D). Single group pre-post studies (Hedges’ g = −1.61, 95% CI [−1.84, −1.38], I² = 1.99%, p = 0.32) seemed to overestimate efficacy, and the greater heterogeneity of groups using placebo controls (Hedges’ g = −1.47, 95% CI [−1.91, −1.03], I² = 74.00%, p = 0.00) was reported. Heterogeneity was lower using low dose (Hedges’ g = −1.20, 95% CI [−1.41, −0.99], I² = 0.00%, p = 0.68) and positive drug controls (Hedges’ g = −1.60, 95% CI [−2.01, −1.19], I² = 0.00%, p = 0.92) and it appears that psilocybin showed superior efficacy to citalopram.

3.3.2. Subgroup analyses

Disorder type: Previous clinical trials suggested that psychedelics were effective not only for depression (Carhart-Harris et al., 2021; Davis et al., 2021; Gukasyan et al., 2022; Majumder et al., 2012; Murphy et al., 2021; Raison et al., 2023; Sloshower et al., 2023; von Rotz et al., 2023), but also for TRD and recurrent depression (Carhart-Harris et al., 2018, 2016a; Daws et al., 2022; Goodwin et al., 2022; G.M. Goodwin et al., 2023a; Lyons and Carhart-Harris, 2018; Osório Fde et al., 2015; Palhano-Fontes et al., 2019; Sanches et al., 2016; Stroud et al., 2018; Wall et al., 2023; Zeifman et al., 2021), in patients for whom general antidepressants are not effective enough. In addition, they had shown promising preliminary results for treating negative emotions in people with SUD (Giovannetti et al., 2020) and terminal illness (Agin-Liebes et al., 2020; D'Souza et al., 2022; Gasser et al., 2014, 2015; Griffiths et al., 2016; Grob et al., 2011; Holze et al., 2023; Lewis et al., 2023; Ross et al., 2021, 2016; Wolfson et al., 2020), as well as in populations with social anxiety disorders (Dos Santos et al., 2021) (Fig. 3). For the population with life-threatening diseases related anxiety and depression (Fig. 3A), psilocybin showed stronger efficacy (Hedges’ g = −1.38, 95% CI [−1.69, −1.07], I2 = 35.94%, p = 0.10) than LSD and MDMA in all types of study designs. Specifically, across three studies types, effect sizes of single group pre-post (Hedges’ g = −1.70, 95% CI [−2.18, −1.21], I2 = 0.00%, p = 0.74), placebo-controlled (Hedges’ g = −1.23, 95% CI [−1.86, −0.60], I2 = 64.01%, p = 0.03), low dose psychedelic-controlled (Hedges’ g = −1.37, 95% CI [−1.80, −0.94], I2 = 0.00%, p = 0.41) indicated different reductions of anxiety and depression. Besides, LSD (Hedges’ g = −0.65, 95% CI [−1.03, −0.27], I2 = 37.89%, p = 0.13) and MDMA (Hedges’ g = −0.69, 95% CI [−1.41, −0.02], I2 = 0.00%, p = 0.72) also indicated slight reductions of anxiety and depression. For the MDD population (Fig. 3B), psilocybin has been most widely reported in the research articles. Across three studies types, effect sizes of single group pre-post (Hedges’ g = −0.73, 95% CI [−1.39, −0.07], I2 = 0.00%, p = 0.62), placebo-controlled (Hedges’ g = −1.67, 95% CI [−2.29, −1.06], I2 = 79.83%, p = 0.00), positive drug-controlled (Hedges’ g = −1.60, 95% CI [−2.01, −1.19], I2 = 0.00%, p = 0.92) indicated different reductions of MDD symptom. There was one article reported ayahuasca (Hedges’ g = −0.54, 95% CI [−1.54, −0.46]) and one reported MDMA (Hedges’ g = −0.88, 95% CI [−1.76, −0.00]) for treating MDD. For the TRD or recurrent MDD population (Fig. 3C), ayahuasca showed stronger efficacy (Hedges’ g = −2.04, 95% CI [−2.50, −1.57], I2 = 0.00%, p = 0.89) than psilocybin (Hedges’ g = −1.51, 95% CI [−1.83, −1.18], I2 = 58.78%, p = 0.02), but there are more articles reported psilocybin than ayahuasca.

Duration of efficacy: When we compared the effects of psychedelics at different time points after the initial dose, the effects could persist for as long as one year, although the intensity of the effects may decrease over time (Fig. 4). Within a month of treatment, psychedelics showed promising efficacy, with a faster onset of action compared to traditional antidepressants. Specifically, psilocybin (Hedges’ g = −1.50, 95% CI [−1.91, −1.10], I² = 76.43%, p < 0.001) showed similar efficacy to ayahuasca (Hedges’ g= −1.46, 95% CI [−2.17, −0.74], I² = 74.11%, p < 0.001) at one month, while MDMA (Hedges’ g = −0.83, 95% CI [−1.33, −0.32], I² = 0.00%, p = 0.92) was slightly weaker. There was only a slight decrease of 9.3% in efficacy at 1 to 3 months after psilocybin administration (Hedges’ g = −1.36, 95% CI [−1.72, −1.00], I²=45.95%, p = 0.08). Thereafter, the efficacy of the psilocybin treatment is almost the same after 3 to 6 months (Hedges’ g = −1.39, 95% CI [−1.63, −1.14], I² = 0.00%, p = 0.91). Nevertheless, the sustainable efficacy of psychedelics persisting six months to a year after administration seems remarkable, for psilocybin (Hedges’ g = −2.05, 95% CI [−2.50, −1.60], I² = 11.76%, p = 0.36) and LSD (Hedges’ g = −1.11, 95% CI [−1.79, −0.42], I² = 28.97%, p = 0.23) and ayahuasca (Hedges’ g= −1.10, 95% CI [−1.62, −0.57], I² = 48.95%, p = 0.16), which may also be due to supplemental dosing.

Negative mood state: When we divided the assessments of psychedelics’ therapeutic effects into three indexes based on the different scales used in previous studies (Fig. 5), psychedelics showed both anxiolytic and antidepressant effects and reduced the risk of suicide. Two reports showed consistent and robust suicide-prevention effects for psilocybin (Hedges’ g = −2.46, 95% CI [−3.55, −1.38]) and ayahuasca (Hedges’ g = −1.81, 95% CI [−2.64, −0.98). Slightly stronger antidepressant effects (Hedges’ g = −1.50, 95% CI [−1.72, −1.28], I² = 59.30%, p < 0.001) than anxiolytic effects (Hedges’ g = −1.34, 95% CI [−1.65, −1.04], I²=0.00%, p = 0.38) was found in the treatment of psilocybin. Other classes of psychedelics also appear to vary in their anxiolytic and antidepressant effects, which may be due to differences in mechanisms of action.

3.4. Part II: psychedelics for the treatment of substance use disorder and PTSD

Both psilocybin and LSD can help patients with SUD to better quit drinking, with three studies showing significant reductions in alcohol abuse and consumption in people treated with psilocybin in combination with psychotherapy (Hedges’ g = −0.45, 95% CI [−0.79, −0.11], I²=12.57%, p = 0.26) (Fig. 6A). Furthermore, six randomized controlled trials on LSD conducted during the 1960s for treating alcoholism reported a pooled odds ratio for improvement with LSD of 1.74 (95% CI [0.99, 2.49], I²=0.00%, p = 0.96) (Fig. 6B). These studies included three types: Placebo-controlled, low dose psychedelic-controlled and positive drug-controlled, with odds ratio of 1.90 (95% CI [0.83, 2.98], I²=0.00%, p = 0.88), 1.95 (95% CI [0.36, 3.54], I²=0.00%, p = 0.59) and 1.30 (95% CI [−0.09, 2.69), respectively. There was no significant heterogeneity within any of the groups, and it appears that positive drug-controlled showed the most conservative efficacy, however, there is no significant difference (p = 0.76).

MDMA-assisted psychotherapy for the treatment of PTSD has recently progressed to phase Ⅲ clinical trials and received breakthrough therapy designation by the Food and Drug Administration (FDA) (Mitchell et al., 2021). Twelve studies from 2012 to 2021 collectively found significant efficacy of MDMA in helping to reduce PTSD symptoms (Hedges’ g = −1.30, 95% CI [−1.75, −0.85], I²=86.01%, p < 0.001) (Fig. 6C). Four of these single-group pre-post studies reported stronger efficacy of MDMA in the treatment of PTSD (Hedges’ g = −2.74, 95% CI [−3.26, −2.22], I²=21.10%, p = 0.33) than placebo-controlled RCTs (Hedges’ g = −0.79, 95% CI [−0.96, −0.62], I²=0.00%, p = 0.54).

3.5. Risk of publication bias

The funnel plot indicated low levels of heterogeneity and a lack of publication bias except for a few outliers (Supplementary Figure 1). A small number of studies have asymmetries, which may suggest that some studies have selected populations that are particularly sensitive to psychedelics, thus exaggerating the experimental effect size. The need for cautious, larger placebo-controlled randomized trials is highlighted by the high rate of publication bias in several domains and by the heterogeneity across studies.

3.6. Sensitivity analyses

Once more than three studies were included, leave-one-out sensitivity tests were conducted for each subgroup to make sure that the overall results were not impacted by a single study. These analyses consisted of repeating the analyses while sequentially excluding each study. Analysis showed that the combined effects of psychedelics on depression, anxiety, suicide intention, alcohol use disorder, and PTSD did not change significantly with several studies specifically omitted, indicating that the overall results obtained in this meta-analysis are robust (Supplementary Figures 2).

3.7. Moderator analyses

Since the meta-analysis covered more than 10 studies, we attempted to explore the sources of heterogeneity using meta-regression. Meta-regressions on dose (p = 0.733), number of study participants (p = 0.306), the age of the subjects (p = 0.209), and gender differences (p = 0.507) did not yield significant results as factors accounting for heterogeneity across studies (Supplementary Figures 3–6).

3.8. Part III: psychedelics for the treatment of specific symptoms and other mental disorders

Many studies have reported that MDMA has a significant therapeutic effect on PTSD. Specific symptoms contributing to this efficacy may include eating disorder symptoms, which have shown a significant reduction in total EAT-26 (Eating Attitudes Test 26) scores following MDMA-assisted therapy among participants with severe PTSD (Brewerton et al., 2022). Furthermore, sleep disturbances are among the most distressing and commonly reported symptoms of PTSD, and Ponte et al. have shown that MDMA can significantly improve sleep quality (Ponte et al., 2021). Finally, Atila et al. found that in central diabetes insipidus patients, oxytocin concentration slightly increased in response to MDMA (Atila et al., 2023).

Psilocybin-assisted therapy has shown marked success in treating depression, and some contributions may reflect reduced obsessive-compulsive symptoms. Moreno et al. observed marked decreases in obsessive-compulsive disorder symptoms in all subjects during their testing sessions (23%−100% decrease in YBOCS score) and improvement generally lasted past the 24-hour time point (Moreno et al., 2006). Furthermore, a pilot study of single-dose psilocybin for body dysmorphic disorder (BDD) showed a significant decrease on the Yale-Brown Obsessive Compulsive Disorder Scale Modified for BDD (BDD-YBOCS) score, with conviction of belief, negative affect, and disability improved after treatment(Schneier et al., 2023). Psilocybin can also reduce both cluster headaches and migraine burden (Schindler et al., 2021, 2022).

Dominguez-Clave et al. suggested a potential therapeutic effect of ayahuasca on emotion regulation and mindfulness capacities (including decentering, acceptance, awareness, and sensitivity to meditation practice) among borderline personality disorder traits (Dominguez-Clave et al., 2019). Kast et al. found LSD had profound analgesic action in severe intolerable pain although the onset of therapeutic action of LSD was somewhat slower than for opioids (Kast and Collins, 1964).

3.9. Adverse effects

Table 3 summarizes adverse reactions reported in 44 out of 70 total articles. The adverse reactions were reported in 8 LSD articles, 5 ayahuasca articles, 17 psilocybin articles, and 14 MDMA articles. Lasting negative or adverse effects resulted from the psychedelic-assisted therapy in about two-thirds of reports (62.9%). The pooled adverse events rate was 58.1% (SD = 24.1), and 19.32 (SD = 10.35) were complaints occurring during the treatment session. These adverse events included headache, nausea, vomiting, dizziness, fatigue, insomnia, nystagmus, euphoria, muscle tension, transient increase in blood pressure, transient anxiety, and delusions, with headache being the most common. Some reports of adverse reactions to a particular psychedelic at the same dose appear to be extremely contradictory, implying that a more rigorous and standardized approach is required.

4. Discussion

We focused on the efficacy and adverse effects of four psychedelics: LSD, ayahuasca (active component DMT), psilocybin, and MDMA. The efficacy may be different due to various conditions being explored with different psychedelics. We found the efficacy of psychedelic-assisted therapy for seven different kinds of disorders: MDD, TRD/recurrent MDD, social anxiety disorder, SUD-related anxiety/depression, life-threatening illness-related anxiety/depression, alcohol use disorder, and PTSD. No serious adverse effects were reported with headache as the most common. This meta-analysis and systematic review provide evidence that psychedelic-assisted treatment is effective, with limited side effects and rapid effects along with the long-term effectiveness of one-dose treatment.

However, we have a limited understanding of the neurobiological mechanisms of psychedelic compounds, their therapeutic potential at scale, and whether their positive outcomes can be separated from undesirable effects (Hess and Gould, 2023). Most studies suggest that psychedelics are 5-HT2A receptor agonists that can lead to profound changes in brain regions such as the hippocampus, neocortex, and amygdala, which are related to perception, cognition, and mood (Kwan et al., 2022). Downstream effects of the 5-HT2A receptor activation on cytomembranes, activation of phospholipase C (PLC), and subsequent synergistic inositol trisphosphate (IP3) activation ultimately lead to increased intracellular calcium concentration and altered neuronal firing (Mastinu et al., 2023). Nevertheless, there are common and subtle differences in the mechanisms of action of different psychedelics (Fig. 7). LSD acts as a 5-HT1A receptor agonist in the nucleus of the locus coeruleus and raphe nuclei (Reissig et al., 2005). MRI scans of the brains of volunteers taking LSD showed surprisingly enhanced neuroactivity with more brain blood flow, higher electrical activity, and denser network communication patterns (Carhart-Harris et al., 2016b). In addition, LSD is thought to be a partial agonist of 5-HT2A receptors, particularly those expressed on neocortical pyramidal cells (González-Maeso et al., 2007).

Ayahuasca, a botanical hallucinogen traditionally used by indigenous groups of the Northwest Amazonregion for ritual and medicinal purposes, has a hallucinogenic impact because it contains a mixture of two plants: the ayahuasca vine Banisteriopsis Caapi (inhibit monoamine oxidase) and the chakruna shrub Psychotria Viridis(containing DMT) (Mastinu et al., 2023). Most of the literatures about ayahuasca we included described the dosage of DMT, but only one mentioned ayahuasca without elucidating the specific dosage of DMT (Table 2). DMT is a partial agonist of the 5-hydroxytryptamine receptors (5-HT2) and its mechanism of action involves the second messenger pathway of phospholipase C and A2 in postsynaptic neurons (Barker, 2018). It can also function at the presynaptic level as an inhibitor of the serotonin transporter(SERT) and vesicular monoamine transporter (2VMAT2) (Carbonaro and Gatch, 2016; Cozzi et al., 2009). Some recent studies have found a similar potential might exist for the short-acting tryptamine 5‑methoxy-N,N-dimethyltryptamine (5-MeO-DMT). 5-MeO-DMT has shown potent and ultra-rapid antidepressant effects and produced significant changes in inflammatory markers, improved affect, and non-judgment (Reckweg et al., 2023; Uthaug et al., 2020). Our study focused on oral administration of traditional ayahuasca, rather than inhalation of vaporized synthetic 5-MeO-DMT. More clinical trials are needed to confirm the anti-inflammatory and antidepressant effects of synthetic 5-MeO-DMT.

Psilocybin has a good affinity with the 5-HT2A receptor (Erkizia-Santamaría et al., 2022) and has been shown to have pharmacological effects by increasing neuroplasticity and neurogenesis via the brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) pathways (Abate et al., 2020). Recent studies have demonstrated that activation of intracellular 5-HT2ARs by DMT and psilocin(produced from psilocybin) leads to sustained increases in dendrite growth and spine density (Hess and Gould, 2023). The prosocial therapeutic effects of MDMA underlie its mechanisms for treatment-resistant mental illness. MDMA is a 5-HT2A receptor agonist, and this effect is thought to contribute to its induced release of DA in the mesolimbic system (Orejarena et al., 2011). MDMA acting on the SERT is necessary but not sufficient for the prosocial effects of MDMA, which also requires 5-HT1B receptor activation (Heifets et al., 2019). MDMA also increases the available concentration of 5-HT via inhibiting SERT, reversing the direction of the membrane transporter and ultimately resulting in the accumulation of 5-HT in the synaptic cleft (Verrico et al., 2007). On the other hand, MDMA promotes the release of monoamines, hormones (oxytocin, cortisol), and other downstream signaling molecules (e.g., BDNF) that dynamically modulate emotional memory circuits (Feduccia and Mithoefer, 2018). In summary, the pharmacology and complexity of mechanisms of action may explain the variability of treatment effects, and further research is needed for clarification.

Although definitive clinical efficacy of psychedelic therapy for depressive and anxiety symptoms has not yet been demonstrated, our review demonstrates that psychedelics show promise against negative emotions within various pathological conditions such as MDD, TRD, terminal disease related negative emotions, SUD, PTSD and social anxiety disorder. Negative emotions like anxiety and depression exist in many people and are manifested in varying severity within many psychiatric disorders. The FDA designated psilocybin as a breakthrough therapy for the treatment of MDD and TRD based on results from a Phase II clinical study released in April 2023. Psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects in a phase 2 trial (Goodwin et al., 2022). In addition, psychedelic-assisted therapy (e.g., ayahuasca) has shown promising results as a treatment for SUD (Giovannetti et al., 2020). Other studies have shown that psilocybin has a rapid and long-lasting effect on anxiety and depression in many cancer patients (Agin-Liebes et al., 2020; Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2021, 2016). Psilocybin and LSD administered in combination with psychotherapy also produced robust decreases in the severity of alcohol addiction compared to placebo and psychotherapy (Bogenschutz et al., 2022; Krebs and Johansen, 2012). Additionally, a phase III clinical trial found that MDMA coupled with psychotherapy was twice as likely as placebo with psychotherapy to induce recovery from PTSD (Mitchell et al., 2021). These early successes indicate an urgent need for more large-scale clinical trials to confirm clinical efficacy and document any adverse effects of psychedelics in assisted therapies.

Our meta-analysis showed significant negative symptom reduction at 1, 3, 6, and 12 months, although the efficacy may weaken over time. A long-term follow-up of 3.2 and 4.5 years after psilocybin-assisted psychotherapy in patients with life-threatening cancer conducted by Stephen Ross indicated sustained efficacy of psilocybin treatment (Ross et al., 2021). We suggest that the underlying neural mechanisms behind this may involve remodeling and persistent changes in functional brain networks. Psilocybin can produce a therapeutic response in patients with refractory depression by increasing the connectivity of functional brain networks (Daws et al., 2022). These significant changes in the structure of brain modules suggest that the immediate effects of psilocybin may be retained. In support of this suggestion, a single dose of psilocybin can persistently induce the formation of dendritic spines in the medial frontal cortex of mice and enhance neuronal connectivity (Shao et al., 2021). This synaptic structural remodeling occurred within 24 h and persisted even after 1 month, potentially providing a long-term integration of experiences and lasting beneficial actions.

The increased risk of suicide in patients with MDD or other mood disorders contributes to high mortality and morbidity rates, and reducing the risk of suicide using psychedelics is quite compelling. Lifetime psilocybin use was associated with lowered odds of lifetime suicidal thinking, planning, and attempts (Jones et al., 2022). Another study showed ayahuasca reduced suicidal ideation (Zeifman et al., 2019). Ketamine also shows rapid antidepressant effects which reduce suicidal ideation (Abbar et al., 2022; Beaudequin et al., 2021; Mkrtchian et al., 2021). However, only two articles evaluating suicidal ideation were included in this meta-analysis, and broader demographic circumstances need to be considered in future studies to make this finding representative.

Although most studies indicate that psychedelic therapy has not resulted in serious life-threatening adverse effects, questions about the safe use of psychedelics remain. For example, Goodwin et al. conducted a phase 2 double-blind trial using single-dose psilocybin for TRD and found that in 233 participants adverse events occurred in 84% of participants in the 25 mg group, 75% of participants in the 10 mg group, and 72% of participants in the 1 mg group (G.M. Goodwin et al., 2023a). In a phase 2, double-blind, randomized, controlled trial of psilocybin involving patients with moderate-to-severe MDD, 87% of patients in the psilocybin group had adverse events (Carhart-Harris et al., 2021). Moreover, adverse events in polydrug ecstasy users with good medical health received MDMA 75 mg in two test days, and MDMA aggravated rather than relieved two negative affect states, anxiety and confusion (Kuypers et al., 2018). A syndrome known as hallucinogen-persisting perception disorder (HPPD) is defined by persistent or recurrent perceptual symptoms that resemble the acute effects of hallucinogens after repeated use of hallucinogens. A wide range of LSD-like substances, cannabis, MDMA, psilocybin, mescaline, and psychostimulants are linked to HPPD (Lev-Ran et al., 2017; Müller et al., 2022; Orsolini et al., 2017). This makes special and secure therapeutic settings essential for intended therapeutic outcomes when using psychedelics. An exploratory survey about psychedelic knowledge and opinions in psychiatrists showed that the most desired topics were potential benefits of psychedelic-assisted therapy, how to conduct psychedelic-assisted therapy, psychedelic pharmacology, and psychedelic side effects (Barnett et al., 2022). Ideally, psychedelics can be utilized as powerful vectors of interpersonal psychotherapy (Ponomarenko et al., 2023), but administration of psilocybin requires careful attention to the setting in which the drug is administered (Messell et al., 2022). MDMA is believed to enhance a therapeutic alliance, thereby facilitating therapist-assisted trauma processing (Sottile and Vida, 2022). MAPS Public Benefit Corporation (“MAPS PBC”) announced submission of new drug application to the FDA for MDMA-assisted therapy for PTSD. If approved, it would be the first psychedelic-assisted therapy approved for PTSD.

It has become evident from over 50 years of illicit hallucinogen use that combining psychedelics with psychotherapy under strict physician supervision is safer than unsupervised long-term use with abuse potential. Moreover, studies in recent years also have shown promising results regarding the use of psychedelics in addiction. For example, psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models (Johnson et al., 2014, 2017). Furthermore, LSD, MDMA, and psilocybin all have shown therapeutic effects in patients with alcohol use disorder or alcoholism (Bogenschutz et al., 2022; Krebs and Johansen, 2012; Ludwig et al., 1969; Sessa et al., 2021). In addition, we summarized the effects of psychedelics in healthy populations (Supplementary Table 2). It was found that 28 out of a total of 37 studies reported positive effects, which included subjective positive effects such as increased positive mood, prosocial behavior, happiness, social relationships, evaluation of the self, anxiolysis, protracted analgesic effect and attenuation of symptoms related to hopelessness and panic-like symptoms; 2 of them reported non-significant results (no improvement or effect on mood); 8 of them mentioned negative effects such as impaired recognition and accuracy of sad and fearful faces, prolonged REM sleeplatency, increased anxiety and confusion, and attenuates the encoding and retrieval of salient details from emotional events (75% derived from MDMA, but it is worth noting that some of the studies also reported positive effects); the other 3 used neutral descriptions such as producing subjective effects, and were well tolerated. In general, psychedelics are well tolerated in healthy populations, but attention should be paid to the negative effects mentioned above. Further research is warranted to define potential indications and safety guidelines.

There are several limitations in this meta-analysis. First is the main problem of heterogeneity, with different types of clinical studies being included and large variations in the doses, regimens, samples, inclusion criteria, and primary endpoints used in different studies. Second, meta-analysis cannot avoid publication bias, which occurs because positive results are more likely to be published, which can significantly overestimate effect sizes. We have excluded all observational studies to minimize this bias. Third are small study sample sizes, improper methodological design, inadequate statistical analysis, and subject inclusions. Among all the articles, 33 studies have less than 30 subjects, resulting in the lack of significant correlations in the meta-regressions. Fourth, because psychedelics can significantly alter perception and even produce hallucinations, the failure of some studies to blind participants and staff may have resulted in biased estimates of effects, making it difficult to ensure the certainty of our evidence. Finally, functional unblinding may still be challenges for researchers attempting to design rigorous, blinded, clinical trials. Placebo effects may be inflating efficacy sizes and psychotherapy trials would similarly have high rates of functional unblinding given how dramatically different these interventions are subjectively experienced by trial participants (Rosenblat et al., 2023). Thus, more cautious, large-scale, placebo-controlled randomized clinical trials of psychedelics are essential.

In conclusion, the present study provides a relatively comprehensive insight into the efficacy and adverse effects of psychedelics in populations with eight types of mental disorders. Our findings suggest that psychedelic-assisted treatment offers a promising new direction for the booming innovations in the treatment of mental disorders. However, treatment with psychedelics still carries some risk of adverse effects and abuse, so the combined use of psychedelics as an adjunctive therapy under the strict supervision of a physician is certainly advisable.

Efficacy and Safety of Psychedelics for Mental Disorders: A Comprehensive Review

Introduction

Mental disorders, such as depression, anxiety disorders, and post-traumatic stress disorder (PTSD), significantly affect global health and place an immense burden on healthcare systems. Millions worldwide live with these conditions, which can profoundly disrupt mood, cognition, motivation, and behavior. While various treatment measures exist, including drug therapy, psychotherapy, and neuromodulation, even the most effective options often show modest efficacy, notable side effects, challenges with discontinuation, and high rates of symptom relapse. This highlights a pressing need for novel and more effective treatments.

Psychedelics, including compounds like lysergic acid diethylamide (LSD), ayahuasca (containing N,Nʹ-dimethyltryptamine, DMT), psilocybin, and 3,4-methylenedioxymethamphetamine (MDMA), have been historically administered in various contexts, including ancient ceremonial practices. During the mid-20th century, these substances were extensively investigated as aids in psychotherapy. Research indicates that psychedelics induce their psychological effects primarily by activating serotonin 2A receptors (5-HT2AR) and modulating neural circuits involved in mood and emotional regulation. Further findings suggest that psychedelics can enhance neuroplasticity, potentially offering a new mechanism for the lasting symptom improvements observed in recent clinical trials.

Evidence suggests that different psychedelics offer varied therapeutic benefits. Psilocybin therapy has shown antidepressant potential, with rapid and sustained effects observed in clinical trials for depression. LSD was used in the 1950s-1970s as an adjunct to psychotherapy, with published studies demonstrating its safety and efficacy in reducing anxiety associated with life-threatening diseases and improving quality of life. Ayahuasca has also demonstrated significant antidepressant effects, particularly in individuals with treatment-resistant depression. MDMA, known for increasing empathy and social engagement, has shown high efficacy in MDMA-assisted behavioral therapy for individuals with severe PTSD, including those with co-occurring conditions like depression and substance use disorders.

This systematic review and meta-analysis synthesized findings from all clinical trials on psychedelic-assisted therapy or monotherapy published after 1960. The review examined the effect sizes of LSD, ayahuasca, psilocybin, and MDMA on mood disorders and other mental disorders, such as alcohol use disorder and PTSD, at primary endpoints. It also analyzed the emotional effects of psychedelics on healthy subjects to evaluate their safety and discussed reported side effects in the treatment of mental illness. The overall aim was to synthesize the best available clinical evidence and propose directions for future research.

Methods

This review followed a preregistered protocol and was designed in accordance with established guidelines for systematic reviews. A comprehensive search of scientific databases, including Web of Science, Embase, EBSCO, and PubMed, was systematically conducted in February 2024. The search strategy focused on terms related to hallucinogens and various psychiatric or mental disorders, with a filter for experimental studies such as randomized controlled trials (RCTs), quasi-RCTs, and controlled clinical trials, including open-label and single-group designs. Study selection was performed by independent researchers, with discrepancies resolved through discussion.

Studies were included if they were published in English in a peer-reviewed journal and involved participants diagnosed with mood disorders (including depression, anxiety, generalized anxiety disorder, major depressive disorder, recurrent MDD, or life-threatening illness-related anxiety/depression), substance use disorders, alcohol use disorder, or PTSD. Participants were exposed to psychedelics as an add-on treatment or monotherapy, and studies assessing adverse reactions were also included. Outcomes were measured using psychological scales before and after psychedelic treatment. Exclusions included animal studies, data published before 1960, abstracts, case series, case reports, observational studies, cross-sectional surveys, or studies lacking sufficient data for analysis or relevant control groups.

Data extraction focused on treatment effects on mental disorders, indicated by pre/post scores of symptomatology using standard measures, as well as statistical significance. Effect sizes were calculated as standardized mean differences or odds ratios, comparing active treatment groups to control groups or pre- versus post-treatment in single-group studies. Key data extracted included authors, publication year, study design, specific disorder, psychedelic drug, outcome measure, sample size, drug dose, number of sessions, control group type, primary endpoint, and main findings, including side effects. Symptom scales most frequently used in the literature were prioritized for extraction. When data were unavailable, corresponding authors were contacted, or graphical extraction was performed.

Statistical analyses used Hedges’ g for continuous outcomes and odds ratios (ORs) for categorical outcomes to calculate effect sizes. All analyses were performed using a random-effect model, accounting for both between-study and within-study variability. Heterogeneity was quantified using the I2 statistic. Subgroup analyses were conducted based on different psychedelics, disorder types, duration of efficacy, and efficacy index. Meta-regression explored heterogeneity sources, including dose, subject age, female proportion, and number of participants. Publication bias was evaluated using funnel plots and Egger's regression test, and sensitivity analyses were performed by sequentially excluding studies to assess result stability.

Results Summary

The initial search yielded 17,780 citations, which were reduced to 126 articles after removing duplicates and screening titles and abstracts. Ultimately, 59 articles were used for meta-analysis, and 67 for systematic reviews. MDMA was most frequently studied for PTSD (18 articles), while psilocybin (28 articles) and ayahuasca (7 articles) had the largest number of articles on treating mood disorders. LSD was explored in six articles for mood disorders and six for alcoholism.

Most studies involved only one or two doses. Psilocybin was the most commonly studied psychedelic (43.6% of articles), followed by MDMA (29.9%), LSD (14.9%), and ayahuasca (11.5%). These psychedelics were investigated across five main groups of individuals: those with depressive disorders, anxiety disorders, PTSD, substance use disorder (SUD)-related anxiety/depression, and life-threatening illness-related anxiety/depression. The average post-treatment evaluation occurred at 11.97 weeks, with follow-up assessments, when available (51.7% of studies), extending up to 54 months. Most studies featured small sample sizes, averaging 23.46 participants, with a mean age of 43.74 years and 53.94% female participants.

Effects on Mood Disorders

Analysis of 35 studies on mood disorders showed that psychedelics generally improved negative mood to some extent. Psilocybin demonstrated the strongest therapeutic effect, followed by ayahuasca and MDMA, while LSD showed a comparatively lower effect, possibly due to the smaller number of included studies. The type of study design influenced reported efficacy, with single-group pre-post studies often overestimating efficacy compared to placebo-controlled trials. Psilocybin studies encompassed a range of designs and appeared to show superior efficacy compared to a common antidepressant.

Regarding specific disorder types, psychedelics proved effective not only for general depression but also for treatment-resistant depression (TRD) and recurrent depression, where conventional antidepressants may be insufficient. They also showed promising preliminary results for addressing negative emotions in individuals with SUD and terminal illnesses, as well as those with social anxiety disorders. For individuals with life-threatening diseases experiencing anxiety and depression, psilocybin demonstrated strong efficacy, with LSD and MDMA also showing slight reductions in symptoms. In populations with major depressive disorder (MDD), psilocybin was the most widely reported, showing varying reductions in symptoms across different study designs. For TRD or recurrent MDD, ayahuasca showed stronger efficacy than psilocybin, although psilocybin was more frequently studied.

When evaluating the duration of efficacy, the effects of psychedelics could persist for as long as one year, though intensity might decrease over time. Within a month of treatment, psychedelics showed promising efficacy with a faster onset of action compared to traditional antidepressants. Psilocybin and ayahuasca showed similar efficacy at one month, while MDMA was slightly less potent. Psilocybin’s efficacy showed only a minor decrease from one to three months, and remained almost consistent from three to six months. Sustained efficacy of psychedelics, particularly psilocybin, LSD, and ayahuasca, persisting six months to a year after administration, appeared remarkable, possibly due to supplemental dosing.

Assessing therapeutic effects based on different symptom scales revealed that psychedelics exhibit both anxiety-reducing (anxiolytic) and antidepressant effects, and can also reduce the risk of suicide. Psilocybin and ayahuasca demonstrated consistent and robust suicide-prevention effects. Psilocybin showed slightly stronger antidepressant effects than anxiolytic effects. Different classes of psychedelics appeared to vary in their anxiolytic and antidepressant effects, which may stem from differences in their mechanisms of action.

Effects on Substance Use Disorder and PTSD

Both psilocybin and LSD can support individuals with substance use disorders in reducing alcohol consumption. Three studies indicated significant reductions in alcohol abuse when psilocybin was combined with psychotherapy. Additionally, six randomized controlled trials on LSD from the 1960s reported improved outcomes for alcoholism, with consistent findings across various control groups.

MDMA-assisted psychotherapy for PTSD has advanced significantly, progressing to phase III clinical trials and receiving breakthrough therapy designation from the Food and Drug Administration (FDA). Twelve studies published between 2012 and 2021 collectively found significant efficacy of MDMA in reducing PTSD symptoms. Single-group pre-post studies generally reported stronger efficacy for MDMA in treating PTSD compared to placebo-controlled randomized controlled trials.

Analysis and Study Limitations

Analysis of potential publication bias indicated generally low levels of heterogeneity and a lack of publication bias, with only a few outliers suggesting that some studies might have included populations particularly sensitive to psychedelics, potentially overstating the experimental effect size. Sensitivity analyses, conducted by sequentially removing each study, confirmed that the overall results for the combined effects of psychedelics on depression, anxiety, suicide intention, alcohol use disorder, and PTSD remained stable, indicating the robustness of the meta-analysis findings. Moderator analyses, which explored factors such as dose, number of study participants, subject age, and gender differences, did not yield significant results accounting for heterogeneity across studies.

Effects on Other Specific Symptoms and Conditions

Beyond mood disorders, substance use disorder, and PTSD, MDMA has shown potential in alleviating specific symptoms. It has been associated with significant reductions in eating disorder symptoms and improvements in sleep quality among participants with severe PTSD. MDMA has also shown a slight increase in oxytocin concentration in certain patients.

Psilocybin-assisted therapy has been linked to marked decreases in obsessive-compulsive disorder symptoms and significant improvements in body dysmorphic disorder symptoms. It has also shown promise in reducing both cluster headaches and migraine burden.

Ayahuasca has been suggested to have a potential therapeutic effect on emotion regulation and mindfulness capacities, particularly in individuals with borderline personality disorder traits. LSD has demonstrated profound analgesic action in severe, intolerable pain, though its onset of therapeutic action was somewhat slower than opioids.

Reported Side Effects

Adverse reactions were reported in 44 out of 70 articles. Lasting negative or adverse effects were noted in approximately two-thirds of reports (62.9%). The overall pooled adverse events rate was 58.1%, with 19.32% of complaints occurring during the treatment session. Common adverse events included headache, nausea, vomiting, dizziness, fatigue, insomnia, nystagmus, euphoria, muscle tension, transient increases in blood pressure, transient anxiety, and delusions. Headache was the most frequently reported adverse event. Some reports on adverse reactions to a particular psychedelic at the same dose were contradictory, highlighting the need for more rigorous and standardized reporting.

Discussion

This review provides comprehensive insights into the efficacy and adverse effects of four psychedelics: LSD, ayahuasca (DMT), psilocybin, and MDMA. The efficacy may differ due to various conditions explored with different psychedelics. The findings indicate that psychedelic-assisted therapy shows promise for various mental disorders, including major depressive disorder (MDD), treatment-resistant depression (TRD)/recurrent MDD, social anxiety disorder, substance use disorder (SUD)-related anxiety/depression, life-threatening illness-related anxiety/depression, alcohol use disorder, and PTSD. Generally, no serious adverse effects were reported, with headache being the most common. This meta-analysis and systematic review provide evidence that psychedelic-assisted treatment is effective, with limited side effects and rapid, long-lasting effects even with single-dose treatment.

The precise neurobiological mechanisms of psychedelic compounds are still being explored. Most studies suggest that psychedelics act as 5-HT2A receptor agonists, leading to profound changes in brain regions involved in perception, cognition, and mood. These effects can lead to increased intracellular calcium concentrations and altered neuronal firing. While commonalities exist, there are subtle differences in the mechanisms of action. For instance, LSD acts as a partial agonist of 5-HT2A receptors, ayahuasca involves compounds that inhibit monoamine oxidase and contain DMT, and psilocybin increases neuroplasticity via brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) pathways. MDMA affects serotonin transporters and promotes the release of monoamines, hormones (like oxytocin), and other signaling molecules (like BDNF). These complex pharmacological actions may explain the variability in treatment effects.

Despite the fact that definitive clinical efficacy for depressive and anxiety symptoms has not yet been fully demonstrated, this review illustrates the promise of psychedelics for negative emotions across various pathological conditions. Regulatory bodies, such as the FDA, have designated psilocybin as a breakthrough therapy for MDD and TRD based on promising phase II clinical study results. Studies have shown psilocybin's rapid and long-lasting effect on anxiety and depression in cancer patients. Psilocybin and LSD administered with psychotherapy have also led to robust decreases in alcohol addiction severity. Additionally, a phase III clinical trial found MDMA coupled with psychotherapy to be highly effective for PTSD. These early successes underscore the urgent need for more large-scale clinical trials to confirm clinical efficacy and thoroughly document any adverse effects.

The increased risk of suicide in individuals with mood disorders contributes to high mortality and morbidity rates, and reducing this risk using psychedelics is compelling. Lifetime psilocybin use has been associated with lowered odds of suicidal thinking, planning, and attempts. Another study indicated that ayahuasca reduced suicidal ideation. While most studies suggest that psychedelic therapy does not result in serious life-threatening adverse effects, questions about the safe use of psychedelics remain. High rates of adverse events have been reported in some trials, often transient and mild. A rare syndrome known as hallucinogen-persisting perception disorder (HPPD), characterized by persistent perceptual symptoms, has been linked to repeated use of various hallucinogens. This highlights the essential need for special and secure therapeutic settings when using psychedelics. Psychedelics are believed to enhance therapeutic alliances, facilitating therapist-assisted trauma processing.

Over 50 years of experience with illicit hallucinogen use suggests that combining psychedelics with psychotherapy under strict physician supervision is safer than unsupervised long-term use. Recent studies have also shown promising results for the use of psychedelics in addiction treatment, such as for smoking cessation and alcohol use disorder. In healthy populations, psychedelics are generally well-tolerated, often producing positive subjective effects like improved mood and prosocial behavior, though some temporary negative effects have been noted.

Several limitations should be considered in this meta-analysis. These include significant heterogeneity across studies due to variations in doses, regimens, sample sizes, inclusion criteria, and primary endpoints. Publication bias, where positive results are more likely to be published, may lead to an overestimation of effect sizes, although observational studies were excluded to minimize this. Many studies also suffered from small sample sizes or methodological design issues, which affected statistical analyses. Furthermore, the challenge of blinding participants and staff in psychedelic trials, due to the drugs' significant perceptual alterations, may introduce bias. Therefore, more cautious, large-scale, placebo-controlled randomized clinical trials of psychedelics are essential to confirm efficacy and establish safety guidelines. In conclusion, this study provides a relatively comprehensive insight into the efficacy and adverse effects of psychedelics across various mental disorders. The findings suggest that psychedelic-assisted treatment offers a promising new direction for innovations in mental disorder treatment. However, treatment with psychedelics still carries some risk of adverse effects and potential for misuse, emphasizing that their use as an adjunctive therapy under strict medical supervision is advisable.

Efficacy and Safety of Psychedelics for Mental Disorders: A Review

Introduction

Mental health conditions like depression, anxiety disorders, and post-traumatic stress disorder (PTSD) significantly impact healthcare systems and society. Hundreds of millions of people worldwide live with depression and anxiety. These conditions involve persistent negative thoughts and emotions, affecting mood, thinking, motivation, and behavior. Current treatments, including medication and psychotherapy, often have limited effectiveness, notable side effects, and high rates of relapse. This highlights a critical need for new and better treatment options.

Psychedelics, such as lysergic acid diethylamide (LSD), ayahuasca (containing DMT), psilocybin, and 3,4-methylenedioxymethamphetamine (MDMA), are substances that interact with serotonin receptors in the brain. They have been used in various contexts for centuries. In the mid-20th century, researchers extensively studied psychedelics for their potential in psychotherapy. Early findings suggested these substances could reduce symptoms in individuals with different forms of depression, anxiety, and even substance dependence. Research indicates that psychedelics influence brain circuits related to mood and emotions, potentially by enhancing neuroplasticity—the brain's ability to reorganize and form new connections. This process may contribute to the lasting improvements observed in recent clinical trials.

The effectiveness of psychedelics can vary depending on the specific substance. Psilocybin has shown rapid and sustained antidepressant effects in trials. LSD, previously explored in the 1950s and 60s, demonstrated reductions in anxiety for individuals with life-threatening illnesses and has also been studied for conditions like alcoholism. Ayahuasca, a traditional Amazonian brew, has been linked to improved well-being and significant antidepressant effects, even in cases of treatment-resistant depression. MDMA, known for increasing empathy and mood, has shown promise for severe PTSD, including cases with co-occurring conditions like depression and childhood trauma.

This systematic review and meta-analysis aimed to combine the findings from clinical trials on psychedelic-assisted therapy or monotherapy since 1960. The review examined the effects of LSD, ayahuasca, psilocybin, and MDMA on mood disorders (depression, anxiety, negative emotions related to substance use or terminal illness) and other mental health conditions like alcohol use disorder and PTSD. The safety of psychedelics was also evaluated by analyzing their emotional effects on healthy individuals. Ultimately, the goal was to summarize the best available evidence and suggest directions for future research.

Methods

This review followed established guidelines for systematic reviews and was preregistered. Researchers systematically searched several scientific databases for relevant studies published in English in peer-reviewed journals. The search included terms related to various psychedelics and a wide range of mental health conditions. Three independent researchers screened the identified articles, resolving any differences through discussion.

Studies were included if they involved adult participants diagnosed with mood disorders, anxiety disorders, major depressive disorder (MDD), recurrent MDD, treatment-resistant depression (TRD), or anxiety/depression related to life-threatening illness, substance use disorder (SUD), alcohol use disorder (AUD), or PTSD. Participants' diagnoses were based on standard diagnostic criteria, and their symptoms were measured using recognized psychological scales before and after treatment. The studies needed to be experimental, including randomized controlled trials (RCTs), quasi-RCTs, or controlled clinical trials. Even single-group studies (pre-post designs) were included to avoid missing relevant evidence, given the challenges of blinding with psychedelics. Studies assessing adverse reactions were also considered. Excluded studies included animal research, outdated data before 1960, abstracts only, case reports, or studies lacking necessary data for analysis or control groups. Articles on healthy subjects or those not suitable for meta-analysis due to data limitations were used for systematic review.

Data extracted from the included studies included author information, publication year, study design (e.g., placebo-controlled, single group), the specific mental disorder treated, the psychedelic drug used, primary outcome measures, sample size, drug dose, number of dosing sessions, control group type, and main findings regarding efficacy and side effects at different time points. Symptom scales frequently used in the literature were prioritized for data extraction. When data were unavailable, corresponding authors were contacted, or data were estimated graphically.

For continuous outcomes, a statistical measure called Hedges’ g was used to standardize effect sizes, accounting for differences in measurement scales. For categorical outcomes, such as the number of people achieving remission, odds ratios were used. A random-effect model was applied for all analyses to account for variability between studies. Study differences were quantified using the I2 statistic. Subgroup analyses explored effects based on psychedelic type, disorder type, duration of efficacy, and outcome measure. Meta-regression investigated factors like dose, participant age, gender proportion, and sample size. Publication bias was assessed using funnel plots and Egger's regression test. Sensitivity analyses, which involved re-running analyses while excluding one study at a time, were performed to ensure result stability.

Results

The initial search yielded over 17,000 citations, which were reduced to 126 articles after removing duplicates and screening. Fifty-nine of these articles were suitable for meta-analysis, and the remaining 67 were used for systematic reviews. MDMA was most studied for PTSD, while ayahuasca and psilocybin had the most articles on mood disorders. LSD was also studied for mood disorders and alcoholism.

Most studies involved a single or two doses of psychedelics. Psilocybin was the most frequently studied psychedelic (43.6%), followed by MDMA (29.9%), LSD (14.9%), and ayahuasca (11.5%). These substances were administered to individuals with depressive disorders, anxiety disorders, PTSD, substance-use-related anxiety/depression, and anxiety/depression linked to life-threatening illnesses. The average post-treatment evaluation occurred about 12 weeks after treatment. For studies with follow-up, the last assessment averaged nearly 10 months after treatment. Most studies involved small sample sizes, averaging around 23 participants. The average age of participants was about 44 years, with slightly more than half being female.

Psychedelics for Mood Disorders

Analyses of 35 studies indicated that various psychedelics generally improved negative mood. Psilocybin showed the strongest therapeutic effect, followed by ayahuasca and MDMA. LSD’s effect appeared lower, possibly due to fewer studies. When considering study designs, single-group pre-post studies often reported stronger efficacy compared to placebo-controlled studies, which might overestimate the true effect. Psilocybin studies were the most diverse in design, showing superior efficacy to a common antidepressant in head-to-head comparisons.

Disorder type: Psychedelics demonstrated effectiveness for various mood-related conditions. For anxiety and depression in individuals with life-threatening illnesses, psilocybin showed strong efficacy across different study designs. LSD and MDMA also indicated some reduction in these symptoms. For major depressive disorder (MDD), psilocybin was the most widely reported, showing varying effects depending on the study design, with placebo-controlled and positive drug-controlled trials indicating substantial symptom reduction. For treatment-resistant depression (TRD) or recurrent MDD, ayahuasca showed stronger efficacy than psilocybin, although more studies focused on psilocybin.

Duration of efficacy: Psychedelic effects could persist for up to a year, though intensity might decrease over time. Within a month of treatment, psychedelics showed promising efficacy with a faster onset compared to traditional antidepressants. Psilocybin and ayahuasca had similar efficacy at one month, while MDMA was slightly less potent. Psilocybin’s efficacy showed only a small decrease between one and six months. Notably, the sustained efficacy of psychedelics for six months to a year after administration appeared significant, potentially due to supplemental dosing.

Negative mood state: Psychedelics demonstrated both anxiety-reducing and antidepressant effects, and also reduced the risk of suicide. Psilocybin and ayahuasca showed robust effects in preventing suicide. Psilocybin had slightly stronger antidepressant effects than anxiety-reducing effects. Other psychedelics also showed varied effects on anxiety and depression, which may be related to their different mechanisms of action.

Psychedelics for Substance Use Disorder and PTSD

Both psilocybin and LSD appeared to help individuals with substance use disorders reduce alcohol consumption. Three studies on psilocybin combined with psychotherapy showed significant reductions in alcohol abuse. Six randomized controlled trials on LSD for alcoholism from the 1960s reported improved outcomes, with varying efficacy across different control types (placebo-controlled, low-dose psychedelic-controlled, and positive drug-controlled). There was no significant difference between these control types.

MDMA-assisted psychotherapy for PTSD has progressed to advanced clinical trials. Twelve studies conducted between 2012 and 2021 collectively found significant efficacy of MDMA in reducing PTSD symptoms. Single-group pre-post studies reported stronger effects than placebo-controlled trials.

Publication Bias and Study Stability

Analysis of publication bias, often shown through funnel plots, indicated low heterogeneity and limited publication bias in most cases, though some asymmetries suggested that certain studies might have selected highly sensitive populations, potentially overestimating effects. The high rate of publication bias in some areas and the variability across studies underscore the need for more rigorous, larger, placebo-controlled randomized trials.

Sensitivity analyses, conducted by sequentially removing each study, confirmed that the overall findings regarding psychedelics’ effects on depression, anxiety, suicidal ideation, alcohol use disorder, and PTSD remained stable and robust. Moderator analyses, which explored factors like dose, number of participants, age, and gender, did not reveal significant relationships accounting for the observed variability across studies, possibly due to small sample sizes in many of the included trials.

Other Therapeutic Applications

Many studies have reported MDMA's significant therapeutic effect on PTSD. This efficacy may extend to specific symptoms like eating disorder symptoms, which showed reduction after MDMA-assisted therapy in individuals with severe PTSD. MDMA also appeared to significantly improve sleep quality, a common issue in PTSD. Furthermore, some research indicates MDMA slightly increases oxytocin concentration in certain patients.

Psilocybin-assisted therapy, known for its success in treating depression, may also reduce obsessive-compulsive symptoms. Studies observed notable decreases in obsessive-compulsive disorder symptoms, with improvements often lasting beyond 24 hours. A pilot study of single-dose psilocybin for body dysmorphic disorder also showed significant symptom reduction. Psilocybin can also help reduce the burden of cluster headaches and migraines.

Ayahuasca has shown potential therapeutic effects on emotion regulation and mindfulness in individuals with borderline personality disorder traits. Early studies also found that LSD had profound pain-relieving effects, though its onset of action was slower than opioids.

Adverse Effects

Adverse reactions were reported in about two-thirds of the included studies, with a pooled adverse event rate of 58.1%. About one-fifth of complaints occurred during the treatment session itself. Common adverse events included headache, nausea, vomiting, dizziness, fatigue, insomnia, nystagmus (involuntary eye movements), euphoria, muscle tension, transient increases in blood pressure, temporary anxiety, and delusions. Headache was the most frequently reported. Contradictory reports on adverse reactions to the same psychedelic at similar doses highlight the need for more standardized reporting.

Discussion

This review focused on the efficacy and adverse effects of LSD, ayahuasca, psilocybin, and MDMA. The effectiveness varied depending on the condition explored. Psychedelic-assisted therapy showed promise for seven different disorders: MDD, TRD/recurrent MDD, social anxiety disorder, SUD-related anxiety/depression, life-threatening illness-related anxiety/depression, alcohol use disorder, and PTSD. Headache was the most common side effect, but no serious adverse events were widely reported. The findings suggest that psychedelic-assisted treatment can be effective, with limited side effects, rapid onset of action, and long-term benefits from a single dose.

Despite these promising results, understanding of the neurobiological mechanisms of psychedelics and their large-scale therapeutic potential remains limited. Most studies suggest psychedelics act as agonists for the 5-HT2A receptor, leading to significant changes in brain regions involved in perception, cognition, and mood. These substances can alter neuronal firing and enhance neuroplasticity. However, each psychedelic has commonalities and subtle differences in how they work. For instance, LSD also affects 5-HT1A receptors, and brain scans show it enhances neural activity and connectivity. Ayahuasca’s effects stem from its components inhibiting monoamine oxidase and containing DMT, which acts on various serotonin receptors and transporters. Psilocybin also binds to the 5-HT2A receptor and increases neuroplasticity. MDMA, while also a 5-HT2A receptor agonist, primarily facilitates the release of serotonin and other monoamines, influencing emotional memory circuits and enhancing pro-social effects crucial for therapy. Further research is needed to clarify the complex pharmacology of these substances.

While definitive clinical efficacy for depressive and anxiety symptoms has not been fully established, this review demonstrates psychedelics' promise against negative emotions across various conditions. Regulatory bodies have recognized this potential, with the FDA designating psilocybin as a breakthrough therapy for MDD and TRD. Early successes in treating SUD, cancer-related anxiety/depression, alcoholism, and PTSD with psychedelics highlight the urgent need for more large-scale clinical trials to confirm efficacy and document any adverse effects.

The meta-analysis showed significant symptom reduction at various follow-up periods, though efficacy may decrease over time. Long-term follow-up studies have indicated sustained benefits from psilocybin treatment, possibly due to brain network remodeling and persistent changes in functional connectivity, suggesting that the immediate effects of psilocybin can be maintained. This synaptic structural remodeling may provide a long-term integration of experiences and lasting beneficial actions.

Reducing suicide risk in individuals with mood disorders is compelling. Studies suggest psilocybin use is associated with lower odds of suicidal ideation and attempts, and ayahuasca has also been shown to reduce suicidal thoughts. While some other substances like ketamine also show rapid antidepressant effects that reduce suicidal ideation, further studies with broader demographic representation are needed regarding psychedelics and suicide prevention.

Despite most studies indicating no serious life-threatening adverse effects, questions about the safe use of psychedelics persist. For example, some trials reported high rates of adverse events, though often transient. Hallucinogen-persisting perception disorder (HPPD), characterized by persistent perceptual symptoms resembling acute hallucinogen effects, is also a concern with repeated use of various psychedelics. These factors emphasize the importance of special and secure therapeutic settings for psychedelic administration. Psychiatrists express a strong interest in understanding the benefits, therapeutic protocols, pharmacology, and side effects of psychedelic-assisted therapy. Ideally, psychedelics can enhance the therapeutic alliance, facilitating trauma processing with therapist assistance.

Over 50 years of illicit hallucinogen use suggest that combining psychedelics with psychotherapy under strict medical supervision is safer than unsupervised long-term use. Recent studies show promising results for psychedelics in addiction treatment, such as psilocybin assisting smoking cessation and LSD, MDMA, and psilocybin showing therapeutic effects in alcohol use disorder. In healthy populations, psychedelics are generally well tolerated, with many studies reporting positive subjective effects like improved mood, pro-social behavior, and anxiety reduction. However, some studies also noted negative effects such as impaired recognition of sad/fearful faces, increased anxiety, and attenuated memory encoding, particularly with MDMA. Further research is warranted to define potential indications and safety guidelines for these substances.

This meta-analysis has limitations. Heterogeneity is a significant issue, with variations in study types, doses, regimens, samples, and inclusion criteria across studies. Publication bias, where positive results are more likely to be published, can overestimate effect sizes, though observational studies were excluded to minimize this. Small study sample sizes (many with fewer than 30 participants) and methodological design issues also limit the certainty of findings and prevent significant correlations in moderator analyses. Additionally, the challenge of truly blinding participants and staff in psychedelic studies, given the profound perceptual changes induced, could lead to biased effect estimates. The strong subjective experience of these interventions makes functional unblinding difficult. Therefore, more cautious, large-scale, placebo-controlled randomized clinical trials are essential for psychedelics.

In conclusion, this study provides a comprehensive overview of the efficacy and adverse effects of psychedelics for eight types of mental disorders. The findings suggest that psychedelic-assisted treatment represents a promising new direction for mental health innovation. However, the use of psychedelics still carries some risks of adverse effects and potential for misuse. Therefore, their combined use as an adjunctive therapy under strict medical supervision is advisable.

Psychedelics for Mental Health: A Review of Effectiveness and Safety

Introduction

Mental health conditions like depression, anxiety, and post-traumatic stress disorder (PTSD) place a significant burden on individuals and healthcare systems worldwide. Millions of people experience depression, which involves ongoing negative thoughts and emotions affecting mood and behavior. Anxiety disorders are marked by excessive fear and avoidance, while PTSD includes re-experiencing trauma, avoidance, and heightened arousal. Current treatments, such as medications and therapies, often have limited success, noticeable side effects, and high rates of relapse. This highlights a clear need for new and more effective treatment options.

Psychedelic substances, such as lysergic acid diethylamide (LSD), ayahuasca (containing DMT), psilocybin, and MDMA (ecstasy), have been used for centuries. In the mid-20th century, these substances were widely studied as part of therapy. Psychedelics interact with the brain's serotonin system, particularly the 5-HT2A receptor, to produce their psychological effects and influence brain pathways related to mood. Research suggests they can improve various mental health conditions by boosting the brain's ability to change and adapt, which might explain the lasting benefits seen in recent studies.

Different psychedelics appear to have varying effects. Psilocybin has shown promise for depression, with rapid and lasting antidepressant effects in studies. LSD was historically used with psychotherapy, showing reductions in anxiety and improvements in quality of life for individuals with life-threatening illnesses, and also explored for addiction. Ayahuasca, a traditional plant-based brew, has demonstrated antidepressant effects, particularly for treatment-resistant depression. MDMA, known for increasing empathy and improving mood, has shown significant effectiveness when used with therapy for severe PTSD.

This comprehensive review and combined analysis of studies collected findings from clinical trials on psychedelic-assisted therapy and single psychedelic treatments published since 1960. The review examined the effectiveness of LSD, ayahuasca, psilocybin, and MDMA on mood disorders, substance use disorders, and PTSD. It also assessed the emotional effects of these substances on healthy individuals to understand their safety, and discussed common side effects in the treatment of mental illness. The overall goal was to bring together the best available clinical evidence and suggest areas for future research.

Methods

The researchers followed a detailed plan, registered beforehand, for this review. They systematically searched several major medical and scientific databases, including Web of Science and PubMed, in February 2024. The search used keywords related to psychedelics and mental health conditions to identify relevant clinical trials. Three independent researchers reviewed the potential studies, resolving any differences through discussion.

Studies were included if they were peer-reviewed English publications involving human participants with mood disorders, anxiety disorders, PTSD, substance use disorders, or anxiety/depression related to terminal illness, diagnosed by standard medical criteria. These studies needed to involve psychedelics as a treatment, either alone or with other therapies, and report on adverse effects. Both randomized controlled trials and other experimental designs were considered, as blinding can be difficult with psychedelics. Studies were excluded if they involved animals, were published before 1960, were only abstracts or case reports, or lacked necessary data for analysis. Studies on healthy individuals or those with insufficient data for combined analysis were included in the broader systematic review but not the meta-analysis.

Data was collected on treatment effects on mental disorders using standard scales measuring symptoms before and after treatment. This included information on study design, type of disorder, psychedelic used, dosage, and side effects. For statistical analysis, the strength of treatment effects was calculated by comparing active treatment groups to control groups, or by looking at changes within the active treatment group over time. Various statistical methods were used to combine results from different studies, assess consistency, and identify factors that might influence the results, such as dose or participant age. Checks were also performed to see if the findings were stable and if there was any bias in which studies were published.

Results

Out of nearly 18,000 initial citations, 126 articles were selected, with 59 used for the main combined analysis (meta-analysis) and 67 for the broader systematic review. Most studies focused on psilocybin for mood disorders, MDMA for PTSD, and LSD or ayahuasca for various mood disorders and alcohol use disorder. These studies typically involved single or two doses of the psychedelics, with an average participant age of about 44 years. Most studies had small sample sizes, averaging around 23 participants, and follow-up periods varied but could extend up to a year or more.

For mood disorders, all four psychedelics (LSD, ayahuasca, psilocybin, and MDMA) showed some improvement in negative mood. Psilocybin demonstrated the strongest effect, followed by ayahuasca and MDMA, with LSD having a somewhat lower effect, possibly due to fewer studies. The effectiveness varied depending on the study design; for example, single-group studies often showed stronger effects than placebo-controlled trials. Psilocybin was effective for general depression, and ayahuasca showed strong effects for treatment-resistant depression. Psychedelics also provided lasting benefits, with effects sometimes persisting for up to a year, and showed both anxiety-reducing and antidepressant effects, as well as reducing the risk of suicidal thoughts.

For substance use disorders, both psilocybin and LSD showed promise in helping individuals reduce alcohol consumption and abuse, especially when combined with psychotherapy. For PTSD, MDMA-assisted therapy demonstrated significant effectiveness in reducing symptoms. Studies, including more rigorous placebo-controlled trials, consistently reported positive results for MDMA in treating PTSD.

Checks for publication bias, which occurs when positive results are more likely to be published, showed generally low levels of bias, although some outliers existed. Sensitivity analyses confirmed that the main findings about psychedelics' effects on depression, anxiety, suicidal thoughts, and substance use were stable and not heavily influenced by any single study. Further analysis explored factors like dose, participant age, and gender, but these did not significantly explain the differences observed across studies.

Beyond primary mental disorders, studies also indicated that psychedelics might help with other specific symptoms. MDMA showed potential for reducing eating disorder symptoms and improving sleep quality in individuals with PTSD. Psilocybin appeared to reduce obsessive-compulsive symptoms and improve body dysmorphic disorder, along with reducing cluster headaches and migraines. Ayahuasca might help with emotion regulation for individuals with borderline personality traits, and LSD showed pain-relieving effects. Regarding safety, adverse reactions were reported in most studies, with common side effects including headache, nausea, dizziness, and temporary increases in blood pressure or anxiety. While most negative effects were short-lived, some reports were contradictory, suggesting a need for more consistent reporting.

Discussion

This review focused on the effectiveness and side effects of LSD, ayahuasca, psilocybin, and MDMA. The findings suggest that psychedelic-assisted therapy shows promise for treating various mental health conditions, including major depressive disorder (MDD), treatment-resistant depression (TRD), anxiety disorders, substance use disorders (SUD), and PTSD. Overall, these treatments appear effective, with rapid and long-lasting effects, and generally limited serious side effects, though headache was commonly reported.

The exact ways psychedelics work in the brain are still being understood. Most studies suggest they affect serotonin receptors, particularly 5-HT2A, leading to changes in brain areas linked to perception, thought, and mood. While all act similarly, each psychedelic has unique effects. LSD, for instance, appears to increase brain activity and connectivity. Ayahuasca, a plant-based brew, affects serotonin and other brain chemicals. Psilocybin may boost the brain's ability to form new connections, and MDMA is known to increase serotonin and other hormones, enhancing social connection and helping with emotional processing. These complex mechanisms likely contribute to the varied treatment effects seen.

While more definitive research is needed, psychedelics show great promise for various conditions. Psilocybin has been recognized by the FDA as a "breakthrough therapy" for major depressive disorder and treatment-resistant depression due to encouraging study results, showing significant symptom reduction. Psychedelic-assisted therapies, including ayahuasca for substance use disorders and psilocybin for anxiety and depression in cancer patients, have shown rapid and lasting positive effects. MDMA combined with psychotherapy has demonstrated high effectiveness for PTSD. The benefits can persist for several months to over a year, possibly due to changes in brain networks and enhanced brain connectivity. Additionally, initial findings suggest that psilocybin and ayahuasca may help reduce suicidal thoughts.

While psychedelics generally do not cause serious life-threatening adverse effects, safety concerns remain. Common side effects reported in trials include headache, nausea, and temporary increases in blood pressure or anxiety. Some individuals may experience negative emotional states or, rarely, a persistent perception disorder (HPPD) after use. This highlights the critical need for these therapies to be administered in carefully controlled, therapeutic settings with professional supervision. Combining psychedelics with psychotherapy, as is common in clinical trials, is considered safer than unsupervised use and is believed to enhance the therapeutic benefits by improving the bond between patient and therapist. Recent progress, such as MDMA's submission for FDA approval for PTSD, shows growing recognition of their potential.

This review has some limitations, including differences across studies in terms of dosages, treatment plans, and participant groups, which can make it hard to combine results perfectly. There is also a possibility of publication bias, where studies with positive results are more likely to be published. Many studies had small sample sizes, and it is challenging to conduct fully blinded trials with psychedelics, which might affect the perception of their effectiveness. Despite these challenges, the findings suggest that psychedelic-assisted treatment is a promising new approach for mental health. However, because these treatments carry some risks, using them as part of therapy under strict medical supervision is highly recommended.

How Psychedelic Medicines May Help Mental Health

Introduction

Mental health problems like depression, anxiety, or PTSD are a big burden on healthcare and society. Many millions of people around the world live with depression and anxiety. Depression means having ongoing negative thoughts and feelings that affect mood, thinking, drive, and actions. Anxiety disorders involve a lot of fear and worry, or avoiding things that seem scary. PTSD is a harmful problem where people relive bad memories, avoid things, and have negative thoughts and feelings after a difficult event.

Today, there are many ways to treat depression and anxiety, like medicines, talking therapies, and other new methods. For PTSD, treatments that work best often involve facing past difficult experiences and certain talking therapies. However, even the best current treatments may not work perfectly. They can have clear side effects, be hard to stop using, and symptoms can come back. This means we need new and better ways to help people.

Psychedelic drugs, like LSD, ayahuasca (which has DMT), psilocybin, and MDMA, have been used in spiritual ways for a very long time. In the 1950s and 1960s, scientists studied these drugs a lot, often using them with talking therapy. They found that psychedelics could make people less sick from different kinds of depression, anxiety, and other mental health issues, including problems with alcohol. New brain studies show that psychedelics mostly work by affecting a brain chemical called serotonin. They can help the brain change and grow, which might explain why people feel better for a long time after using them in studies.

Evidence shows that psychedelics can help with depression, but different ones work in different ways. Psilocybin therapy shows promise for depression, with effects that can be felt quickly and last a while. LSD was used with talking therapy in the past. One study showed that LSD therapy helped people with anxiety from life-threatening illnesses, making them less anxious and improving their quality of life. LSD has also been looked at for alcohol problems and anxiety from serious illnesses. Ayahuasca, a natural plant drink from the Amazon, can make people feel better and may help with depression. It has shown good results for people with depression that is hard to treat. MDMA, found in the party drug ecstasy, makes people feel more understanding, social, and improves mood. It can also help people work through difficult feelings. Some studies suggest that using MDMA might lower the risk of depression. MDMA therapy with talking therapy works very well for people with severe PTSD, even those who also have other issues like depression or past trauma.

In this study, scientists looked at the results of all clinical trials on psychedelics used for treatment since 1960. They checked how well psychedelics (LSD, ayahuasca, psilocybin, and MDMA) helped with mood problems (depression, anxiety, negative feelings in people with drug or alcohol problems, or serious illnesses) and other mental issues like alcohol problems and PTSD. They also looked at how psychedelics affected healthy people to see how safe they were. Lastly, they discussed the side effects of psychedelics when used for mental illness. The goal was to bring together the best available evidence and suggest what to study next.

Methods

The plan for this study was registered beforehand. The steps for finding and choosing studies followed specific guidelines to make sure the work was done well.

Scientists looked through many health databases in early 2024. They used specific search words to find studies about psychedelics and mental health. Three different researchers checked the studies, and any disagreements were solved by talking it over.

Studies were included if they were published in English in a respected science journal. They had to involve adults with certain mood problems, anxiety, or depression that met official health guidelines. People with depression that was hard to treat or severe PTSD were also included. Studies where psychedelics were given alone or with other treatments were chosen. Studies that looked at bad reactions to psychedelics were also included. The study included different types of research, like those where people were randomly assigned to groups (randomized controlled trials) and those that looked at how people felt before and after treatment. These less strict studies were included because it is hard to do fully "blind" studies with psychedelics (where no one knows who got the drug). It was important that studies measured how people felt using common mental health tests before and after treatment. Studies were not included if they were about animals, were published before 1960, were only short summaries, were about single cases, or were missing key information. Some studies that could not be used for combining results were still looked at to get a general overview.

From each study, the researchers gathered information like the authors, when it was published, how the study was set up, the specific mental health problem it looked at, the psychedelic drug used, how results were measured, the number of people in the study, the drug dose, how many times it was given, what kind of control group was used (like a placebo group), and the main findings and side effects. They also collected details about the people in the study, like their age and gender. If information was missing, they tried to contact the study authors. If that did not work, they used special tools to get the numbers from graphs in the papers.

To understand the results, scientists used special math tools to measure how big the treatment effects were. For most results, they measured the difference in scores before and after treatment, or between the drug group and the control group. For results like the number of people who got better, they used a different measure. They looked at how different the studies were from each other. They also looked at smaller groups of studies (for example, by type of psychedelic or type of problem) to see if effects were different. They checked if things like the dose, age of people, or number of people in the study affected the results. They also used special tests to see if studies with good results were more likely to be published, which can make the overall effects seem better than they are. To make sure the results were strong, they also re-ran the analysis many times, each time removing one study to see if it changed the overall findings.

Results

Study Selection

The process for choosing studies is shown in a diagram. At first, many thousands of articles were found. After removing duplicates, over ten thousand titles and summaries were checked. Based on the rules for what to include and exclude, 126 articles were finally chosen. Out of these, 59 were used to combine results in a "meta-analysis," and 67 were used for a general "systematic review."

Characteristics of Studies

This study looked at many different types of research. MDMA was used in the most articles (18) for treating PTSD. Ayahuasca (7 articles) and psilocybin (28 articles) were most often used for mood problems. LSD had 6 articles for mood problems and 6 for alcohol problems. Most studies used only one or two doses of the drug. Psilocybin was the most studied psychedelic, followed by MDMA, LSD, and then ayahuasca.

These psychedelics were used in five main groups of people: those with depression, anxiety, PTSD, anxiety or depression linked to drug or alcohol use, and anxiety or depression linked to life-threatening illnesses. The last two groups usually involved people feeling very bad mentally. The studies covered two types of depression: major depression and depression that keeps coming back or is hard to treat.

On average, people were checked about 12 weeks after treatment. For about half of the studies, there was a follow-up check about 9 and a half months after treatment. Except for a few larger studies, most had small numbers of people, with an average of about 23 participants. The average age of people in the studies was around 44 years old, and a little more than half were women. More details were shown when looking at smaller groups within the studies.

Part I: psychedelics for the treatment of mood disorders

Overall Effect Sizes

Scientists looked at the treatment effects across 35 studies for four psychedelics: LSD, ayahuasca, psilocybin, and MDMA. Overall, all these psychedelics helped improve negative moods to some extent. Psilocybin showed the strongest effect among the four, followed by ayahuasca and MDMA. LSD showed a smaller effect, possibly because there were fewer studies that looked at it.

Because this study gathered many different types of clinical research, even those that were not random controlled trials, scientists also looked at how the study design affected the results for mood problems. Studies on LSD only looked at people before and after treatment, without a control group. For ayahuasca, studies that looked at people before and after treatment showed stronger effects than those with a placebo control. A similar pattern was seen for MDMA. Psilocybin had many different types of study designs. Studies looking at people before and after treatment seemed to show a stronger effect than might be true. Studies using a placebo control showed more varied results. Studies that compared psilocybin to a low dose of the drug or to another active drug showed less varied results. It seemed that psilocybin worked better than a common antidepressant called citalopram.

Subgroup Analyses

Studies have suggested that psychedelics help not only with common depression but also with depression that is hard to treat or comes back often, especially when usual antidepressants don't work well enough. They also show early promise for helping with negative feelings in people who misuse drugs or alcohol, and those with life-threatening illnesses. Psychedelics have also shown good results for social anxiety.

For people with anxiety and depression linked to life-threatening diseases, psilocybin showed a stronger effect than LSD and MDMA across all study types. LSD and MDMA also showed some reduction in anxiety and depression. For people with major depression, psilocybin was most often studied. Studies using a placebo control showed the strongest effect for psilocybin in reducing depression symptoms. There was also one study on ayahuasca and one on MDMA for treating major depression. For people with depression that is hard to treat or comes back often, ayahuasca showed a stronger effect than psilocybin, but more articles reported on psilocybin.

When scientists looked at how long the effects of psychedelics lasted after the first dose, they found that the effects could continue for up to a year, though they might become a little weaker over time. Psychedelics started to work faster than common antidepressants. Within one month of treatment, psilocybin and ayahuasca showed similar strong effects, while MDMA was a bit weaker. For psilocybin, the effects only slightly lessened between 1 to 3 months, and then stayed about the same from 3 to 6 months. It seemed that the lasting effects of psychedelics, particularly psilocybin, LSD, and ayahuasca, from six months to a year after treatment were quite good. This might be because people had extra doses.

When scientists looked at how psychedelics helped different negative feelings, they found effects on anxiety, depression, and even a reduced risk of suicide. Two studies showed very strong effects of psilocybin and ayahuasca in preventing suicide. For psilocybin treatment, the antidepressant effects were slightly stronger than the anxiety-reducing effects. Other psychedelics also seemed to have different effects on anxiety and depression, which might be because they work in slightly different ways in the brain.

Part II: psychedelics for the treatment of substance use disorder and PTSD

Both psilocybin and LSD can help people with substance use problems to stop drinking. Three studies showed that psilocybin, when used with talking therapy, greatly reduced alcohol misuse. Also, six random controlled trials from the 1960s on LSD for alcohol problems showed that people improved about 1.7 times more often with LSD. These studies included different types of comparisons, and it appeared that comparisons to other active drugs showed the most careful effect size, but there was no big difference between the types of studies.

MDMA therapy with talking therapy for PTSD has moved to advanced clinical trials and has been recognized as a breakthrough treatment by a health agency. Twelve studies between 2012 and 2021 found that MDMA greatly helped reduce PTSD symptoms. Studies that looked at people before and after treatment showed a stronger effect of MDMA in treating PTSD than the studies that compared it to a placebo.

Risk of Publication Bias

A special chart (funnel plot) showed that studies had similar results overall and that there wasn't much bias from studies with positive results being more likely to be published. However, a few studies stood out, which might mean they picked people who would react very strongly to psychedelics, making the treatment seem more effective than it truly is. This highlights the need for more careful, larger studies with placebo controls.

Sensitivity Analyses

When scientists tested the results by removing one study at a time (if there were more than three studies in a group), they found that the overall effects of psychedelics on depression, anxiety, suicide thoughts, alcohol use problems, and PTSD did not change much. This means that the overall findings of this study are reliable.

Moderator Analyses

Since many studies were included, scientists tried to understand why some study results were different from others. However, things like the dose of the drug, the number of people in the study, their average age, or the percentage of women in the study did not explain these differences.

Part III: psychedelics for the treatment of specific symptoms and other mental disorders

Many studies have shown that MDMA helps a lot with PTSD. It can also reduce problems like eating disorder symptoms and greatly improve sleep quality, which is often a big issue for people with PTSD. One study also found that MDMA slightly increased a hormone called oxytocin.

Psilocybin therapy has worked very well for depression. It might also reduce symptoms of obsessive-compulsive disorder (OCD). One study found a large decrease in OCD symptoms, which often lasted for more than a day. Also, an early study showed that a single dose of psilocybin helped people with body dysmorphic disorder, making them feel better about their body image and reducing their distress. Psilocybin can also help reduce the burden of severe headaches like cluster headaches and migraines.

Studies suggest that ayahuasca might help people with traits of borderline personality disorder to control their emotions better and be more mindful (aware of the present moment, accepting). Another study found that LSD had strong pain-relieving effects for severe pain, though it took a bit longer to work than strong painkillers.

Adverse Effects

Reports from 44 out of 70 articles talked about bad reactions. About two-thirds of the reports mentioned lasting negative or bad effects from psychedelic-assisted therapy. On average, about 58% of people had bad events, and about 19% of those were complaints that happened during the treatment session. These bad effects included headache, nausea, throwing up, dizziness, tiredness, trouble sleeping, unusual eye movements, feeling overly happy, muscle tightness, a temporary rise in blood pressure, temporary anxiety, and false beliefs. Headache was the most common problem. Some reports of bad reactions to the same psychedelic at the same dose seemed very different, which means a stricter way of reporting is needed.

Discussion

This study looked closely at how well and how safely four psychedelics—LSD, ayahuasca (which has DMT), psilocybin, and MDMA—worked. Their effects might differ because they were studied for various conditions. The study found that therapy with psychedelics helps with seven different mental health problems: major depression, depression that is hard to treat or comes back often, social anxiety, anxiety or depression linked to substance use, anxiety or depression linked to life-threatening illnesses, alcohol use disorder, and PTSD. No serious life-threatening side effects were reported, and headaches were the most common issue. This study shows that psychedelic-assisted treatment works well, has limited side effects, and can have quick and lasting effects even from a single dose.

However, scientists still do not fully understand how these drugs work in the brain, how widely they can be used, and if their good effects can be separated from unwanted ones. Most studies suggest that psychedelics affect a specific brain chemical receptor (5-HT2A). This can lead to big changes in brain areas related to how we see, think, and feel. Different psychedelics work in similar but slightly different ways. For example, LSD also affects another serotonin receptor and can make brain activity and connections stronger. Ayahuasca contains DMT, which affects serotonin, and other compounds that help the DMT work. Psilocybin connects well with the 5-HT2A receptor and helps the brain's ability to change and grow. MDMA helps people feel more social and affects serotonin and other brain chemicals and hormones. The complex ways these drugs work might explain why their effects vary, and more research is needed to understand this better.

While the strong ability of psychedelic therapy to help with depression and anxiety is not fully proven yet, this study shows they are promising for negative feelings in many different health conditions. The Food and Drug Administration (FDA) has given psilocybin a special "breakthrough therapy" status for treating major depression and depression that is hard to treat. Studies show that a single dose of psilocybin can greatly lower depression scores, though it might cause side effects. Psychedelic-assisted therapy, like with ayahuasca, also shows promise for helping with substance use problems. Other studies found that psilocybin had a fast and long-lasting effect on anxiety and depression in many cancer patients. Psilocybin and LSD used with talking therapy greatly reduced severe alcohol problems compared to placebo and therapy. Also, a large study found that MDMA combined with talking therapy was twice as likely to help people recover from PTSD compared to a placebo with therapy. These early good results mean that more large studies are urgently needed to confirm how well these therapies work and to record any bad effects.

This study found that major symptoms were greatly reduced at 1, 3, 6, and 12 months after treatment, though the effects might lessen over time. A long-term check-up for people with life-threatening cancer who received psilocybin therapy showed that the benefits lasted for several years. This might be because the drugs help the brain's connections change and stay changed. Psilocybin can make new connections in the brain and make existing ones stronger, which might lead to lasting good effects. This brain change happened quickly and stayed for at least a month, possibly helping to make the good experiences last.

The higher risk of suicide in people with depression or other mood problems leads to many deaths and illnesses. Reducing this risk with psychedelics is very important. Studies have shown that using psilocybin might lower the chances of having suicidal thoughts, plans, and attempts. Another study found that ayahuasca reduced suicidal thoughts. Other drugs like ketamine also show fast antidepressant effects that reduce suicidal thoughts. However, this study only included two articles that looked at suicidal thoughts, so future studies need to include more types of people to confirm this finding.

Even though most studies suggest that psychedelic therapy does not cause serious, life-threatening bad effects, there are still questions about using psychedelics safely. For example, one study found that in people with severe depression, 84% of those who got 25 mg of psilocybin had bad events, compared to 72% in a very low dose group. Another study found that 87% of patients in the psilocybin group had bad events. Also, in a study with people who used ecstasy, MDMA made anxiety and confusion worse for some. A condition called Hallucinogen-Persisting Perception Disorder (HPPD) means people have lasting or returning visual problems like those from hallucinogens after using them often. HPPD is linked to many types of psychedelics. This means that special and safe treatment places are very important when using psychedelics for therapy. Experts in mental health are very interested in learning how to do psychedelic-assisted therapy safely. Ideally, psychedelics can be a strong tool in talking therapy, but psilocybin must be given in a carefully controlled setting. MDMA is believed to help people connect better with their therapist, which makes it easier to work through trauma. A group called MAPS PBC has asked the FDA to approve MDMA-assisted therapy for PTSD. If approved, it would be the first psychedelic-assisted therapy for PTSD.

From over 50 years of illegal hallucinogen use, it has become clear that using psychedelics with talking therapy under strict doctor supervision is safer than using them for a long time without supervision, which can lead to misuse. Also, recent studies show good results for using psychedelics to help with addiction. For example, psilocybin may be a helpful addition to current ways to quit smoking. LSD, MDMA, and psilocybin have all shown good effects in people with alcohol problems. Also, this study looked at how psychedelics affect healthy people. It found that most studies showed positive effects, such as better mood, social behavior, happiness, and less anxiety or pain. A few studies reported no big change in mood, and some mentioned negative effects like trouble recognizing faces or increased anxiety. Overall, psychedelics are usually well tolerated in healthy people, but the negative effects need attention. More research is needed to figure out when and how to use them safely.

This study has some limits. First, the studies included were often very different in drug doses, treatment plans, and the people studied. Second, it is hard to avoid "publication bias," which means studies with positive results are more likely to be published, possibly making the effects seem stronger than they are. Scientists tried to lessen this by not including studies based on simple observations. Third, many studies had small numbers of people, so it was hard to find clear patterns in the data. Fourth, because psychedelics greatly change what people experience, it is hard to do studies where people don't know if they got the drug or a placebo. This can lead to biased results. Also, people often know if they've received a powerful drug, which means a "placebo effect" might make the treatment seem more effective. Because of these reasons, more careful, large, randomly controlled studies with psychedelics are greatly needed.

In short, this study gives a good look at how well psychedelics work and what their bad effects are for people with eight different mental health problems. The findings suggest that treatment with psychedelics offers a promising new way to help people with mental health issues. However, using psychedelics still comes with some risk of bad effects and misuse, so it is definitely best to use them as an added therapy under the close supervision of a doctor.